Azetidine-2-carboxylic acid is an unusual amino acid, the (S)-enantiomer of which is known to be useful in the synthesis of inter alia high molecular weight polypeptides and in particular as an analogue of the well known amino acid proline.
This amino acid is of limited availability from natural sources, and in nature is found only as the (S)-enantiomer. The development of an efficient and economic synthetic method for producing both the pure racemic compound and either of the individual (R) or (S) single enantiomers is therefore desirable.
Previously documented chiral syntheses of (S)-azetidine-2-carboxylic acid include a five step preparation via homoserine lactone, starting from N-tosyl protected L-methionine (see e.g. Japanese Patent Application No. 14457/74 and Bull. Chem. Soc. Jpn. (1973) 46, 699) and a five step preparation via L-4-amino-2-chlorobutyric acid, starting from L-2,4-diaminobutyric acid (see Biochem. J. (1956) 64, 323).
Previously documented preparations of enantiomerically-pure azetidine-2-carboxylic acid from the racemate involve long and relatively complicated multi-step methodology.
For example, a four step preparation involving the protection, resolution and subsequent deprotection of racemic azetidine-2-carboxylic acid is known from J. Heterocyclic Chem. (1969) 6, 993. In this method, N-carbobenzoxy-protected racemic azetidine-2-carboxylic acid is resolved, using L-tyrosine hydrazide as resolution agent, and then isolated before a final deprotection step. This process has the disadvantage that L-tyrosine hydrazide is expensive as well as only being available in one enantiomeric form. This prior art also reports the additional problem that attempts to use common resolving agents in the resolution of several N-acyl derivatives of racemic azetidine-2-carboxylic acid results in the production of non-crystallizable oils.
Surprisingly we have found that N-acyl derivatives of azetidine-2-carboxylic acids may be efficiently and economically resolved using the common and inexpensive resolving agent 1-phenylethylamine.